The invention relates to carboxamide-substituted benzimidazole derivatives, methods of their manufacture, their use in the treatment of certain disease conditions, and pharmaceutical compositions comprising such compounds.
Benzimidazole derivatives are known from the prior art as active substances with valuable pharmaceutical properties. Thus, International Patent Application WO 98/37075 discloses, in addition to other bicyclic heterocycles, benzimidazoles which can be effectively used to prevent and treat venous and arterial thrombotic diseases by virtue of their thrombin-inhibiting activity.
In contrast to the benzimidazole derivatives as described above and known from the prior art, which are useful for the treatment of thrombotic diseases, the present invention provides compounds having tryptase-inhibitory activity which can be used to prevent and treat inflammatory and/or allergic diseases.
The present invention provides carboxamide-substituted benzimidazole derivatives of general formula (I) 
wherein
R1 denotes a group selected from among C1-C6-alkyl, C2-C6-alkenyl and C2-C6-alkynyl, which may optionally be mono-, di- or trisubstituted by one or more of the groups hydroxy, C1-C4-alkoxy, CF3, phenoxy, COOH, halogen, xe2x80x94CO(C1-C4-alkoxy), xe2x80x94COxe2x80x94NR5R6, xe2x80x94NR5R6 or C1-C4-alkoxy-phenoxy, or
phenyl-C1-C4-alkyl, which may optionally be mono-, di- or trisubstituted by one or more of the groups hydroxy, C1-C4-alkoxy, carboxy, halogen, C1-C4-alkoxycarbonyl or CF3, or
a 5- or 6-membered, saturated or unsaturated heterocycle linked directly or via a C1-C4-alkylene bridge, which may contain one or two heteroatoms selected from among oxygen, nitrogen or sulphur and which may optionally be substituted by C1-C4-alkyl or benzyl;
R2 denotes xe2x80x94C(xe2x95x90NH)NH2 or xe2x80x94CH2xe2x80x94NH2;
R3 denotes a C1-C6-alkyl, C1-C6-hydroxyalkyl or C1-C4-alkoxy-C1-C4-alkyl group which may be mono- or disubstituted by one, two or three of the groups xe2x80x94NR5R6, xe2x80x94C(xe2x95x90NH)NH2 or xe2x80x94NHxe2x80x94C(xe2x95x90NH)NH2, or
a 5-, 6- or 7-membered, saturated or unsaturated heterocycle linked directly or via a C1-C4-alkylene bridge or a C2-C4-alkenylene bridge, which may contain one, two or three heteroatoms selected from among oxygen, nitrogen or sulphur and which may optionally be mono- or disubstituted by hydroxy, C1-C4-alkyl, xe2x80x94COOxe2x80x94C1-C4-alkyl, xe2x80x94CONH2, benzyl, diphenylmethyl, phenyl or pyridylmethyl, pyridyl, and wherein the phenyl substituent may be mono-, di- or trisubstituted by one or more groups selected from among C1-C4-alkyl, C1-C4-alkoxy, halogen, C1-C4-alkyl-halogen and xe2x80x94NH2,
cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each of which may be mono- or disubstituted by one or two of the groups xe2x80x94NR5R6, xe2x80x94C(xe2x95x90NH)NH2 or xe2x80x94NHxe2x80x94C(xe2x95x90NH)NH2, or phenyl-C1-C4-alkyl or naphthyl-C1-C4-alkyl, which may optionally be substituted at the alkylene bridge by xe2x80x94NR5R6 and may be mono- or disubstituted at the phenyl ring by one or two of the groups xe2x80x94NO2, xe2x80x94NR5R6, xe2x80x94C1-C4-alkyl-NR5R6, xe2x80x94C(xe2x95x90NH)NH2 or xe2x80x94NHxe2x80x94C(xe2x95x90NH)NH2,
R4 denotes hydrogen or C1-C6-alkyl, which may optionally be mono- or disubstituted by one or two groups selected from among furanyl, benzofuranyl, thiophenyl, benzothiophenyl, anthracenyl, phenyl, pyridyl and naphthyl, while the substituents phenyl and naphthyl may in turn be mono-, di- or trisubstituted by one or more of the groups selected from among C1-C4-alkyl, C1-C4-alkoxy, halogen, C1-C4-alkyl-halogen, xe2x80x94NH2, xe2x80x94NH(C1-C4-alkyl), xe2x80x94N(C1-C4-alkyl)2, NO2, hydroxy, xe2x80x94CF3, xe2x80x94NHCOxe2x80x94C1-C4-alkyl, xe2x80x94COOH, xe2x80x94COO(C1-C4-alkyl), xe2x80x94CONH2, xe2x80x94CONH(C1-C4-alkyl), xe2x80x94CON(C1-C4-alkyl)2, xe2x80x94CONH(C1-C4-alkyl)xe2x80x94COO(C1-C4-alkyl) and phenyl-C1-C6-alkyl;
R5 and R6, which may be identical or different, denote hydrogen, C1-C4-alkyl, phenyl, pyridyl or benzyl, which may optionally be substituted by a group selected from among halogen, halo-C1-C4-alkyl, xe2x80x94OH, C1-C4-alkyl, xe2x80x94Oxe2x80x94C1-C4-alkyl, xe2x80x94Oxe2x80x94C1-C4-alkyl, xe2x80x94COxe2x80x94Oxe2x80x94C1-C4-alkyl, xe2x80x94NO2, phenyl, pyrrolidin-1-yl, piperidin-1-yl, xe2x80x94NH2, xe2x80x94NHxe2x80x94C1-C4-alkyl, xe2x80x94N(C1-C4-alkyl)2 and xe2x80x94C(xe2x95x90NH)NH2xe2x80x94NH2,
optionally in the form of the tautomers, the racemates, the enantiomers, the diastereomers and the mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof.
It has been found, surprisingly, that compounds of formula I have tryptase-inhibitory activity and that they may be used to treat disease conditions in which tryptase inhibitors have therapeutic value.
Preferred compounds according to the invention are the compounds of general formula (I),
wherein
R1 denotes C1-C6-alkyl, which may optionally be mono-, di- or trisubstituted by one or more of the groups hydroxy, C1-C4-alkoxy, CF3, phenoxy, COOH, halogen, xe2x80x94CO(C1-C4-alkoxy), xe2x80x94COxe2x80x94NR5R6, xe2x80x94NR5R6 or C1-C4-alkoxy-phenoxy, or
R2 denotes xe2x80x94C(xe2x95x90NH)NH2 or xe2x80x94CH2xe2x80x94NH2;
R3 denotes a C1-C6-alkyl group, which may be mono- or disubstituted by one or two of the groups xe2x80x94NR5R6, xe2x80x94C(xe2x95x90NH)NH2 or xe2x80x94NHxe2x80x94C(xe2x95x90NH)NH2, or
a 5-, 6- or 7-membered, saturated or unsaturated heterocycle linked directly or via a C1-C4-alkylene bridge, which may contain one, two or three heteroatoms selected from among oxygen, nitrogen or sulphur and may optionally be mono- or disubstituted by hydroxy, C1-C4-alkyl, benzyl, phenyl or pyridyl, and wherein the phenyl substituent may be substituted by one of the groups selected from among C1-C3-alkyl, C1-C3-alkoxy, halogen, trifluoromethyl and NH2,
cyclopropyl, cyclopentyl or cyclohexyl, each of which may be mono- or disubstituted by one or two of the groups xe2x80x94NR5R6, xe2x80x94C(xe2x95x90NH)NH2 or xe2x80x94NHxe2x80x94C(xe2x95x90NH)NH2, or
phenyl-C1-C4-alkyl or naphthyl-C1-C4-alkyl, which may optionally be substituted by xe2x80x94NR5R6 at the alkylene bridge and may be mono- or disubstituted at the phenyl ring by one or two of the groups xe2x80x94NO2, xe2x80x94NR5R6, xe2x80x94C1-C4-Alkyl-NR5R6, xe2x80x94C(xe2x95x90NH)NH2 or xe2x80x94NHxe2x80x94C(xe2x95x90NH)NH2,
R4 denotes hydrogen or C1-C6-alkyl, which may optionally be mono- or disubstituted by one or two groups selected from among phenyl, pyridyl and naphthyl, wherein the substituents phenyl and naphthyl may in turn be substituted by one of the groups selected from among C1-C4-alkyl, C1-C4-alkoxy, halogen, xe2x80x94C1-C4-alkyl-halogen, xe2x80x94NH2;
R5 and R6, which may be identical or different, denote hydrogen, C1-C4-alkyl, pyridyl or benzyl, which may optionally be substituted by a group selected from among xe2x80x94OH, xe2x80x94Oxe2x80x94C1-C3-alkyl, xe2x80x94NO2, phenyl, pyrrolidin-1-yl, xe2x80x94NH2, xe2x80x94NHxe2x80x94C1-C4-alkyl, xe2x80x94N(C1-C4-alkyl)2 and xe2x80x94C(xe2x95x90NH)NH2,
optionally in the form of the tautomers, the racemates, the enantiomers, the diastereomers and the mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof.
Also preferred are carboxamide-substituted benzimidazole derivatives of general formula (I),
wherein
R1 denotes C1-C4-alkyl, which may optionally be mono-, di- or trisubstituted by one or more of the groups hydroxy, C1-C4-alkoxy, CF3, phenoxy, COOH, halogen, xe2x80x94CO(C1-C4-alkoxy), xe2x80x94COxe2x80x94NR5R6, xe2x80x94NR5R6 or C1-C4-alkoxy-phenoxy, or
R2 denotes xe2x80x94C(xe2x95x90NH)NH2 or xe2x80x94CH2xe2x80x94NH2;
R3 denotes a C1-C4-alkyl group, which may be mono- or disubstituted by one or two of the groups xe2x80x94NR5R6, xe2x80x94C(xe2x95x90NH)NH2 or xe2x80x94NHxe2x80x94C(xe2x95x90NH)NH2, or
a 5-, 6- or 7-membered, saturated or unsaturated heterocycle linked directly or via a methylene or ethylene bridge, which may contain one or two heteroatoms selected from among oxygen or nitrogen and may optionally be substituted by methyl or benzyl; naphthylmethyl, benzyl or phenylethyl, which may optionally be substituted by xe2x80x94NR5R6 at the alkylene bridge and may be substituted at the phenyl ring by a group selected from among xe2x80x94NR5R6, xe2x80x94C1-C4-alkyl-NR5R6, xe2x80x94C(xe2x95x90NH)NH2 and xe2x80x94NHxe2x80x94C(xe2x95x90NH)NH2,
R4 denotes hydrogen or C1-C5-alkyl, which may optionally be mono- or disubstituted by one or two groups selected from among pyridyl, phenyl and naphthyl;
R5 and R6, which may be identical or different, denote hydrogen, methyl, ethyl, propyl, butyl, pyridyl or benzyl, which may optionally be substituted by a group selected from among xe2x80x94OH, methoxy, xe2x80x94NO2, phenyl, pyrrolidin-1-yl, xe2x80x94NH2, xe2x80x94NH-methyl, xe2x80x94N(methyl)2, xe2x80x94NH-ethyl, xe2x80x94N(ethyl)2 and xe2x80x94C(xe2x95x90NH)NH2,
optionally in the form of the tautomers, the racemates, the enantiomers, the diastereomers and the mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof.
Particularly preferred are carboxamide-substituted benzimidazole derivatives of general formula (I), wherein
R1 denotes methyl, ethyl, propyl or butyl, preferably methyl;
R2 denotes xe2x80x94C(xe2x95x90NH)NH2 or xe2x80x94CH2xe2x80x94NH2, preferably xe2x80x94C(xe2x95x90NH)NH2;
R3 denotes a C2-C4-alkyl group, which may be mono- or disubstituted by one or two of the groups xe2x80x94NR5R6, xe2x80x94C(xe2x95x90NH)NH2 or xe2x80x94NHxe2x80x94C(xe2x95x90NH)NH2, or
a 6-membered, saturated or unsaturated heterocycle linked via a methylene or ethylene bridge, which contains one or two nitrogen atoms and may optionally be substituted by methyl or benzyl;
naphthylmethyl, benzyl or phenylethyl, which may optionally be substituted by xe2x80x94NR5R6 at the alkylene bridge and which are substituted at the phenyl ring by a group selected from among xe2x80x94NR5R6, xe2x80x94C1-C4-alkyl-NR5R6, xe2x80x94C(xe2x95x90NH)NH2 and xe2x80x94NHxe2x80x94C(xe2x95x90NH)NH2,
R4 denotes hydrogen or an alkyl group selected from among methyl, ethyl, propyl, butyl and pentyl, which may optionally be mono- or disubstituted by one or two groups selected from among pyridyl, phenyl and naphthyl;
R5 and R6, which may be identical or different, denote hydrogen, methyl, ethyl, propyl, butyl, pyridyl or benzyl, which may optionally be substituted by a group selected from among xe2x80x94OH, methoxy, xe2x80x94NO2, phenyl, pyrrolidin-1-yl, xe2x80x94NH2, xe2x80x94NH-methyl, xe2x80x94N(methyl)2 and xe2x80x94C(xe2x95x90NH) NH2,
optionally in the form of the tautomers, the racemates, the enantiomers, the diastereomers and the mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof.
Also particularly preferred are carboxamide-substituted benzimidazole derivatives of general formula (I), wherein
R1 denotes methyl, ethyl or propyl, preferably methyl;
R2 denotes xe2x80x94C(xe2x95x90NH)NH2 or xe2x80x94CH2xe2x80x94NH2, preferably xe2x80x94C(xe2x95x90NH)NH2;
R3 denotes methyl which is substituted by a group selected from among pyridylamino, benzylamino, N-benzyl-N-methylamino, N-(amidinobenzyl)amino, N-(amidinobenzyl)-N-methyl-amino, N-(dimethylaminobenzyl)amino, (pyrrolidin-1-ylbenzyl)amino and N-(dimethylaminobenzyl)-N-methyl-amino, or
an alkyl group selected from among ethyl and propyl, which may be mono- or disubstituted by one or two groups selected from among xe2x80x94NH2 and xe2x80x94NHxe2x80x94C(xe2x95x90NH)NH2, or
a heterocycle linked via an ethylene bridge, selected from among piperidine, morpholine and piperazine, which may optionally be substituted by methyl, benzyl or diphenylmethyl;
phenylethyl, which may optionally be substituted by xe2x80x94NH2 at the ethylene bridge and is substituted at the phenyl ring by a group selected from among pyrrolidin-1-yl, xe2x80x94NH2, xe2x80x94N(methyl)2, xe2x80x94CH2xe2x80x94NH2 and xe2x80x94C(xe2x95x90NH)NH2;
R4 denotes hydrogen, methyl, ethyl, propyl, butyl, pentyl, benzyl, pyridylmethyl, naphthalinylmethyl or diphenylpropyl,
optionally in the form of the tautomers, the racemates, the enantiomers, the diastereomers and the mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof.
Of particular importance according to the invention are carboxamide-substituted benzimidazole derivatives of general formula (I), wherein
R1 denotes methyl, ethyl or propyl, preferably methyl;
R2 denotes xe2x80x94C(xe2x95x90NH)NH2 or xe2x80x94CH2xe2x80x94NH2, preferably xe2x80x94C(xe2x95x90NH)NH2;
R3 denotes methyl, which is substituted by a group selected from among N-(amidinobenzyl)amino, N-(amidinobenzyl)-N-methyl-amino, N-(dimethylaminobenzyl)amino, (pyrrolidin-1-ylbenzyl)amino and N-(dimethylaminobenzyl)-N-methyl-amino, or
a piperidine linked via an ethylene bridge, which may optionally be substituted by benzyl;
phenylethyl, which may optionally be substituted by xe2x80x94NH2 at the ethylene bridge and is substituted by xe2x80x94C(xe2x95x90NH)NH2 at the phenyl ring;
R4 may denote hydrogen, methyl, butyl, benzyl, naphthalinylmethyl or diphenylpropyl,
optionally in the form of the tautomers, the racemates, the enantiomers, the diastereomers and the mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof.
Particularly preferred are the compounds of general formula (IA) 
wherein
R3 denotes methyl which is substituted by a group selected from among N-(amidinobenzyl)amino, N-(amidinobenzyl)-N-methyl-amino, N-(dimethylaminobenzyl)amino, (pyrrolidin-1-ylbenzyl)amino, and N-(dimethylaminobenzyl)-N-methyl-amino, or
a piperidine or piperazine linked via an ethylene bridge, which may optionally be substituted by benzyl;
phenylethyl which may optionally be substituted by xe2x80x94NH2 at the ethylene bridge and which is substituted at the phenyl ring by xe2x80x94C(xe2x95x90NH)NH2;
R4 denotes hydrogen, methyl, butyl, benzyl, naphthalinylmethyl or diphenylpropyl, optionally in the form of the tautomers, the racemates, the enantiomers, the diastereomers and the mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof.
In addition to the abovementioned compounds of general formula (I) the present invention further relates to compounds which, because of a functionality which can be cleaved in vivo, are only converted into the therapeutically effective compounds of general formula (I) by the body after they have been taken by the patient. Such compounds are known as prodrugs. According to another aspect, therefore, the invention relates to prodrugs of general formula (II) 
wherein
R1 and R4 may have the meanings given hereinbefore and
R3 may be as hereinbefore defined or may denote C1-C4-alkyl , which is substituted by a group selected from among xe2x80x94C(xe2x95x90NOH)NH2, xe2x80x94C(xe2x95x90NCOOxe2x80x94C1-C12-alkyl)NH2 or xe2x80x94C(xe2x95x90NCOOxe2x80x94C1-C8-alkyl-phenyl)NH2;
R7 may denote hydroxy, xe2x80x94COOxe2x80x94C1-C12-alkyl, xe2x80x94CO-phenyl, xe2x80x94CO-pyridyl or xe2x80x94COOxe2x80x94C1-C8-alkyl-phenyl, whilst in the abovementioned group the phenyl ring may be substituted by C1-C4-alkyl, C1-C4-alkoxy, OH, halogen or CF3,
optionally in the form of the tautomers, the racemates, the enantiomers, the diastereomers and the mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof.
Preferred are prodrugs of general formula (II), wherein
R1 and R4 may be as hereinbefore defined and
R3 may have the meanings given above or denotes C1-C4-alkyl, which is substituted by a group selected from among xe2x80x94C(xe2x95x90NOH)NH2, xe2x80x94C(xe2x95x90NCOOxe2x80x94C1-C6-alkyl)NH2 or xe2x80x94C(xe2x95x90NCOOxe2x80x94C1-C6-alkyl-phenyl)NH2;
R7 may denote hydroxy, xe2x80x94COOxe2x80x94C1-C6-alkyl, xe2x80x94CO-phenyl, xe2x80x94CO-pyridyl or xe2x80x94COOxe2x80x94C1-C6-alkyl-phenyl, whilst in the abovementioned group the phenyl ring may be substituted by C1-C4-alkyl, C1-C4-alkoxy, OH, halogen or CF3,
optionally in the form of the tautomers, the racemates, the enantiomers, the diastereomers and the mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof.
Particularly preferred are prodrugs of general formula (II), wherein
R1, R3 and R4 may be as hereinbefore defined and
R7 may denote hydroxy, methoxycarbonyl, ethoxycarbonyl, propyloxycarbonyl, butyloxycarbonyl, benzoyl, benzyloxycarbonyl or nicotinoyl,
optionally in the form of the tautomers, the racemates, the enantiomers, the diastereomers and the mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof.
The term alkyl groups (including those which are part of other groups) unless otherwise specified, denotes branched and unbranched alkyl groups having 1 to 12 carbon atoms, preferably 1 to 8 carbon atoms, most preferably having 1 to 6 carbon atoms. The following are mentioned by way of example: methyl, ethyl, propyl, butyl, pentyl, hexyl etc. Unless otherwise stated, the terms propyl, butyl, pentyl or hexyl given above also include all the possible isomeric forms. For example, the term propyl includes the two isomeric groups n-propyl and iso-propyl, the term butyl includes n-butyl, iso-butyl, sec. butyl and tert.-butyl, the term pentyl includes isopentyl, neopentyl etc. In some cases, common abbreviations will be used to denote the abovementioned alkyl groups, such as Me for methyl, Et for ethyl etc.
Examples of alkenyl groups (including those which are part of other groups) are branched and unbranched alkenyl groups having 2 to 6 carbon atoms, preferably 2 to 4 carbon atoms, provided that they have at least one double bond, for example the abovementioned alkyl groups as well, provided that they have at least one double bond, such as, for example, vinyl (so long as no unstable enamines or enol ethers are formed), propenyl, iso-propenyl, butenyl, pentenyl, hexenyl.
Examples of alkynyl groups (including those which are part of other groups) are alkynyl groups having 2 to 6 carbon atoms, provided that they have at least one triple bond, for example ethynyl, propargyl, butynyl, pentynyl, hexynyl.
The term halogen generally denotes fluorine, chlorine, bromine or iodine.
Examples of 5- ,6- or 7-membered, saturated or unsaturated heterocycles which may contain nitrogen, oxygen or sulphur as heteroatoms include for example furan, tetrahydrofuran, tetrahydrofuranone, xcex3-butyrolactone, xcex1-pyran, xcex3-pyran, dioxolan, tetrahydropyran, dioxan, thiophene, dihydrothiophene, thiolan, dithiolan, pyrrole, pyrroline, pyrrolidine, pyrazole, pyrazoline, pyrazolidine, imidazole, imidazoline, imidazolidine, triazole, tetrazole, pyridine, piperidine, pyridazine, pyrimidine, pyrazine, piperazine, triazine, tetrazine, morpholine, thiomorpholine, diazepan, oxazole, isoxazole, oxazine, thiazole, isothiazole, thiadiazole, oxadiazole and pyrazolidine, unless otherwise specified in the definitions, whilst the heterocycle may be substituted as specified in the definitions.
xe2x80x9cxe2x95x90Oxe2x80x9d denotes an oxygen atom linked via a double bond.
The present invention further relates to the use of the above-defined compounds of general formula (I) and of the prodrugs of general formula (II) for preparing a pharmaceutical composition for the treatment of diseases in which tryptase inhibitors may have a therapeutic value. It is preferred according to the invention to use the compounds of general formula I as described above, for preparing a pharmaceutical composition for the prevention and/or treatment of bronchial asthma, allergic rhinitis, allergic conjunctivitis, atopic dermatitis, urticaria, allergic otitis, allergic gastro-intestinal disorders, Crohn""s disease, ulcerative colitis, anaphylactic shock, septic shock, shock lung (ARDS) and arthritis.
It is also advantageous to use the compounds of general formula (I) as mentioned above for preparing a pharmaceutical composition for the prevention and/or treatment of fibroses such as lung fibrosis, fibrosing alveolitis and scarring, collagenoses such as lupus erythematodes and sclerodermia as well as arteriosclerosis, psoriasis and neoplasm.
The substituted benzimidazole derivatives of formula (I) and the prodrugs of general formula (II) may be synthesised by various methods. Possible approaches based on and using conventional methods of chemical synthesis are illustrated hereinafter by way of example. Diagram 1 shows a possible method of producing the basic benzimidazole structure of the compounds according to the invention. 
Diagram 1:
Starting from the 2-halo-5-nitro-anilines (1), aminolysis may be carried out first, to obtain the diaminonitrobenzenes (2) according to Diagram 1 (step i). The aminolysis of the compounds (1) with the primary amines R1xe2x80x94NH2 is carried out in suitable organic solvents such as for example dimethylsulphoxide, N,N-dimethylformamide, N-methylpyrrolidone, acetone or optionally in water or alcohols at ambient temperature or in a temperature range of 30-80xc2x0 C., preferably 40-50xc2x0 C.
The reaction of the compounds (2) with p-cyanophenylpropionic acid leads to the nitro-benzimidazoles (3, step ii) by reaction with p-cyanophenylpropionic acid in the presence of dehydrating reagents. The reaction is optionally carried out in a solvent or mixture of solvents such as methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene/tetrahydrofuran or dioxan. Suitable dehydrating agents include for example isobutyl chloroformate, tetraethyl orthocarbonate, trimethyl orthoacetate, 2,2-dimethoxypropane, tetramethoxysilane, phosphorus oxychloride, thionylchloride, trimethylchlorosilan, phosphorus trichloride, phosphorus pentoxide, ethyl 1,2-dihydro-2-ethoxy-quinoline-1-carboxylate (EEDQ), 1,2-dihydro-2-i-propyloxy-quinoline-1-carboxylate (IIDQ), N,Nxe2x80x2-dicyclohexylcarbodiimide, N,Nxe2x80x2-dicyclohexylcarbodiimide/N-hydroxysuccinimide, N,Nxe2x80x2-dicyclohexylcarbodiimide/1-hydroxy-benzotriazole, 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium-tetrafluoroborate, 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium-tetrafluoroborate/1-hydroxy-benzotriazole, N,Nxe2x80x2-carbonyldiimidazole or triphenylphosphine/carbon tetrachloride. In some cases it may be beneficial to add a base such as pyridine, 4-dimethylaminopyridine, N-methyl-morpholine or triethylamine. The reaction is usually performed at temperatures between 0 and 150xc2x0 C., preferably at temperatures between 20 and 120xc2x0 C.
The nitrobenzimidazole derivatives (3) which may be obtained according to the procedure described above may be reductively converted into the amino-benzimidazoles (4) (step iii, Diagram 1). The reduction of the nitro group to form the compounds (3) is carried out for example by catalytic hydrogenation in organic solvents such as for example methanol, ethanol, isopropanol, tetrahydrofuran, optionally also in admixture with dimethylformamide, ethyl acetate, dioxan or acetic acid, at elevated hydrogen pressure or at normal pressure at temperatures between 0-50xc2x0 C., preferably at 20-40xc2x0 C. Suitable catalysts are the conventional hydrogenation catalysts. Palladium and Raney nickel are preferred. According to the invention, palladium is preferred. Palladium on charcoal (5%) is particularly preferred as catalyst. An alternative method of reducing the nitro compounds (3) envisages using reduction agents such as Na2S2O4 or SnCl2. This reaction is carried out in protic, water-miscible organic solvents such as short-chained alcohols (methanol, ethanol, isopropanol) or in a mixture of the abovementioned solvents with water, optionally with acetic acid, dimethylformamide or ethyl acetate. The reaction is usually carried out at elevated temperature, preferably at the reflux temperature of the solvent or mixture of solvents used. After all the starting compounds (3) have been converted working up is done in the usual way. The compounds (4) may be purified for example by crystallisation from non-polar organic solvents such as diethylether, petroleum ether, optionally mixed with ethyl acetate. Starting from the benzimidazoles (4) which may be obtained according to Diagram 1, the compounds (5) according to Diagram 2 are formed by reacting with the compounds R4xe2x80x94Nu, where Nu denotes a nucleofugic leaving group such as for example chlorine, bromine, iodine, methanesulphonate, methyltriflate, p-toluenesulphonate etc. Alternatively, the compounds (5) may be obtained starting from the compounds (4) by reductive amination, by reacting with correspondingly substituted ketones or aldehydes under reductive conditions. 
Diagram 2:
In order to react the compounds (4) with R4xe2x80x94Nu according to step iv the following procedure may be used. A compound (4) is dissolved in a polar solvent, such as dimethylformamide, dimethylactamide, methylene chloride, tetrahydrofuran, preferably dimethylformamide and most preferably anhydrous, optionally absolute dimethylformamide. The solution thus obtained is mixed with a base and the corresponding alkylating agent R4xe2x80x94Nu. Suitable bases include the alkali metal- or alkaline earth metal carbonates of lithium, sodium, potassium and calcium such as sodium carbonate, lithium carbonate, potassium carbonate, calcium carbonate and preferably potassium carbonate. It is also possible to use the alkali metal- or alkaline earth metal hydroxides of lithium, sodium, potassium, magnesium, calcium, but preferably sodium hydroxide, potassium hydroxide, lithium hydroxide and calcium hydroxide in alcohol or water. The reaction mixture is stirred for 0.5-8 h, preferably 1-4 h at elevated temperature, preferably at 50-120xc2x0 C., particularly at the reflux temperature of the solvent used. After conversion is complete the resulting mixture is worked up in the usual way and the crude product obtained is purified by crystallisation or chromatography on silica gel.
If the compounds (5) are obtained from the compounds (4) by reductive amination, the following method is used. The compound (4) is dissolved in a suitable solvent such as for example dichloromethane, dichloroethane, methanol, ethanol, tetrahydrofuran or toluene and between 0-60xc2x0 C., preferably at 20-40xc2x0 C. the corresponding carbonyl compound is added in the presence of an acid, preferably a carboxylic acid, most preferably a short-chained carboxylic acid, best of all acetic acid. Then a suitable reduction agent is added. Reduction agents which may be used according to the invention are Na[HB(OAc)3], Na[BH3CN], NaBH4, Pd/Cxe2x80x94H2, preferably Na[HB(OAc)3]. After working up in the conventional way, the product is purified by crystallisation or chromatography on silica gel.
The intermediates of general formula (III) may be obtained from the compounds (5), as shown in Diagram 3, by acylation (step v). 
Diagram 3:
The reaction of the compounds (5) with the carboxylic acids R3xe2x80x94COOH to obtain the intermediates of general formula (III) may be carried out in a solvent or mixture of solvents such as methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene/tetrahydrofuran or dioxan, optionally in the presence of a dehydrating agent, e.g. in the presence of isobutyl chloroformate, tetraethyl orthocarbonates, trimethyl orthoacetate, 2,2-dimethoxypropane, tetramethoxysilan, thionylchloride, trimethylchlorosilan, phosphorus trichloride, phosphorus pentoxide, N,Nxe2x80x2-dicyclohexylcarbodiimide, N,Nxe2x80x2-dicyclohexylcarbodiimide/N-hydroxysuccinimide, N,Nxe2x80x2-dicyclohexylcarbodiimide/1-hydroxy-benzotriazole, 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium-tetrafluoroborate, 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium-tetrafluoroborate/1-hydroxy-benzotriazole, N,Nxe2x80x2-carbonyldiimidazole or triphenylphosphine/carbon tetrachloride, and optionally with the addition of a base such as pyridine, 4-dimethylaminopyridine, N-methyl-morpholine or triethylamine, conveniently at temperatures between 0 and 150xc2x0 C., preferably at temperatures between 0 and 100xc2x0 C. Alternatively the intermediates of general formula (III) may also be obtained by standard methods by reacting with correspondingly activated carboxylic acid derivatives R3xe2x80x94COX (with X=halide, alkoxy, etc.) in the abovementioned solvents or mixtures of solvents in the presence of bases such as pyridine, 4-dimethylaminopyridine, N-methyl-morpholine or triethylamine.
According to step vi the compounds of general formula (I) according to the invention may be obtained from the intermediates (III). In order to prepare the compounds of general formula (I) according to the invention wherein R2 denotesxe2x80x94C(xe2x95x90NH)NH2, different methods may be used.
A compound of general formula (I) is obtained for example by treating a compound of general formula (III) with a corresponding alcohol such as methanol, ethanol, n-propanol, isopropanol or benzylalcohol, optionally mixed with another organic solvent such as for example chloroform, nitrobenzene or toluene in the presence of an acid such as hydrochloric acid or by reacting a corresponding amide with a trialkyloxonium salt such as triethyloxonium tetrafluoroborate in a solvent such as methylene chloride, tetrahydrofuran or dioxan at temperatures between xe2x88x9210 and 50xc2x0 C., but preferably at 0-20xc2x0 C. and subsequent aminolysis with alcoholic ammonia solution, for example. Alternatively, the compounds of general formula (I) may be obtained by reacting a compound of general formula (III) with sulphur nucleophils such as e.g. hydrogen sulphide, ammonium or sodium sulphide, sodium hydrogen sulphide, carbon disulphide, thioacetamide or bistrimethylsilylthioether, optionally in the presence of bases such as triethylamine, ammonia, sodium hydride or sodium alkoxide in solvents such as methanol, ethanol, water, tetrahydrofuran, pyridine, dimethylformamide or 1,3-dimethyl-imidazolidin-2-one at 20-100xc2x0 C. and subsequently treating with a suitable methylating agent such as e.g. methyliodide or dimethylsulphate in a solvent such as acetonitrile or acetone at temperatures between xe2x88x9210 and 50xc2x0 C., but preferably at 0-20xc2x0 C. and subsequently treating with ammonia, ammonium carbonate or ammonium chloride in a suitable alcohol, such as for example methanol, ethanol, isopropanol etc. at temperatures between xe2x88x9210 and 50xc2x0 C., but preferably at 0-20xc2x0 C.
The compounds of general formula (I) according to the invention may also be obtained by treating a compound of general formula (III) with lithium hexamethyldisilazide in a suitable organic solvent such as e.g. tetrahydrofuran at temperatures between xe2x88x9220 and 50 xc2x0 C., but preferably at 0-20xc2x0 C. and subsequently hydrolysing with dilute hydrochloric acid at 0-5xc2x0 C. Another alternative method of obtaining compounds of general formula (I) comprises treating a compound of general formula (III) with ammonium chloride and trimethylaluminium in a suitable organic solvent such as e.g. toluene at temperatures between 20 and 150xc2x0 C., but preferably at 110xc2x0 C.
Compounds of general formula (I) wherein R2 denotes xe2x80x94CH2xe2x80x94NH2 may be obtained from the intermediates (III) for example by catalytic hydrogenation on Raney nickel. These reactions are preferably carried out in protic organic solvents such as short-chained alcohols (methanol, ethanol or isopropanol) at temperatures between 10-40xc2x0 C., preferably at 20-30xc2x0 C. under normal pressure.
A compound of general formula (II) is obtained for example by treating a compound of general formula (III, Diagram 3, step vii) with hydroxylamine in the presence of carbonates or alkoxides of alkali or alkaline earth metals in solvents such as methanol, ethanol, n-propanol or isopropanol, optionally mixed with dioxan or tetrahydrofuran. The alkoxides may be prepared from the appropriate alkali metals or metal hydrides and the corresponding alcohol. The reaction is preferably carried out at 20-100xc2x0 C., most preferably at the boiling temperature of the solvent used. Compounds of general formula (II) may alternatively be obtained by treating a compound of general formula (III) with a corresponding alcohol such as methanol, ethanol, n-propanol, isopropanol or benzylalcohol in the presence of an acid such as hydrochloric acid or by reacting a corresponding amide with a trialkyloxonium salt such as triethyloxonium-tetrafluoroborate in a solvent such as methylene chloride, tetrahydrofuran or dioxan at temperatures between xe2x88x9210 and 50xc2x0 C., but preferably at 0-20xc2x0 C. and subsequently treating with hydroxylamine in the presence of bases in a suitable alcohol, such as methanol, ethanol, isopropanol etc. at temperatures between xe2x88x9210 and 50xc2x0 C., but preferably at 0-20xc2x0 C.
A compound of general formula (I) is obtained for example by treating a compound of general formula (II, Diagram 3, step viii) with hydrogen in the presence of hydrogenation catalysts such as Raney nickel or rhodium/aluminium oxide in water or methanol optionally with the addition of acids such as hydrochloric acid or methanesulphonic acid or by treating with hydrogen in the presence of palladium/charcoal in acetic acid/acetic anhydride at 20-50xc2x0 C. and 1-5 bar hydrogen pressure, preferably at ambient temperature and normal pressure.
The acyl- or alkoxycarbonyl prodrugs (II) of the compound of general formula (I) are obtained by reacting the compounds of general formula (I) with the corresponding acid chlorides in the presence of bases such as e.g. triethylamine, N-methylmorpholine, diethylisopropylamine or DBU in a suitable solvent such as methylene chloride, chloroform, tetrahydrofuran, acetonitrile, dimethylformamide or dimethylsulphoxide.
In accordance with their central importance in the synthesis of the compounds of general formula (I) according to the invention and in the synthesis of the prodrugs of general formula (II), the invention relates in another aspect to the intermediates of general formula (III) 
wherein the groups R1, R3 and R4 may be as hereinbefore defined. The compounds of general formula (III) are valuable intermediate products for preparing the benzimidazole derivatives of general formula (I) according to the invention as well as the prodrugs of general formula (II) according to the invention.
By virtue of their pharmacological properties the compounds according to the invention may be used as pharmaceutical compositions, particularly as pharmaceutical compositions having a tryptase-inhibiting activity. They may be used in any circumstances where tryptase inhibitors may be of therapeutic benefit. It is preferred according to the invention to use compounds of formula (I) for preparing a pharmaceutical composition for the prevention and/or treatment of inflammatory and/or allergic diseases. It is particularly preferred to use the compounds of general formula I as described above, for preparing a pharmaceutical composition for the prevention and/or treatment of bronchial asthma, allergic rhinitis, allergic conjunctivitis, atopic dermatitis, urticaria, allergic otitis, allergic gastro-intestinal disorders, Crohn""s disease, ulcerative colitis, anaphylactic shock, septic shock, shock lung (ARDS) and arthritis.
It is also advantageous to use the compounds of general formula (I) as mentioned above for preparing a pharmaceutical composition for the prevention and/or treatment of fibroses such as lung fibrosis, fibrosing alveolitis and scarring, collagenoses such as lupus erythematodes and sclerodermia as well as arteriosclerosis, psoriasis and neoplasm.